Isolated porcine bronchi provide a reliable model for development of bronchodilator anti‐muscarinic agents for human use

Background and purpose: In human airways, muscarinic acetylcholine receptors (mAChRs) exert a predominant role in the control of airways resistance and anti‐muscarinic agents are currently included in the pharmacological treatment of chronic obstructive pulmonary disease (COPD). However, the development of more effective mAChR antagonists is hampered by considerable species variability in the ultrastrucural and functional control of airway smooth muscle, making extrapolation of any particular animal model questionable. This study was designed to characterize the mAChRs in a bronchial preparation from pigs, animals considered to provide close models of human biology. Experimental approach: Smooth muscle bronchial strips were examined by electron microscopy in order to compare their neuromuscular structure with that of human bronchi and used to study the affinity of a series of selective mAChR antagonists, estimated as pK i s in competition binding assays with NMS and pA 2, by Schild analysis, in contractile experiments. Key results: Pharmacodynamic binding parameters and affinity profiles of a series of antagonists were consistent with the presence of a majority of M 2  mAChRs along with a minor population of M 3  mAChRs. Functionally, the highly significant correlation between postjunctional pA 2 affinities and corresponding affinity constants at human recombinant M 1 –M 5 subtypes indicated that smooth muscle contraction in porcine bronchi, as in human bronchi, was dependent on the M 3 subtype. Conclusion and implications: Based on the characterization of mAChRs, isolated porcine bronchi provide an additional experimental model for development of mAChR antagonists for the treatment of human airway dysfunctions. British Journal of Pharmacology (2008) 154 , 1611–1618; doi: 10.1038/bjp.2008.208 ; published online 2 June 2008